New heart failure RCT: Update on BeAT-HF in the US

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Bruno Ray
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1 New heart failure RCT: Update on BeAT-HF in the US Michael R. Zile, MD Charles Ezra Daniel Professor of Medicine Medical University of South Carolina Chief, Division of Cardiology RHJ Department of Veterans Affairs MC Charleston, South Carolina Chair, Executive Steering Committee BEAT-HF Study

2 Phase III Beat-HF Study: Randomized, Controlled Trial of Baroreflex Activation Therapy (BAT) in Patients with HFrEF Ineligible for CRT Presentation Goals Clinical Evidence for Development in Heart Failure Novel Trial Design Status of BEAT-HF Study 2

3 Clinical Evidence Development in Heart Failure and Hypertension Stage Heart Failure Hypertension Clinical Rationale Preclinical First In Man CE Mark / Phase II US Phase III Pivotal Georgakopoulos et al, J Cardiac Fail 2012 Sabbah et al, Curr Cardiol Rep 2012 Halbach et al, Expert Rev Cardiovasc Ther 2014 Zucker et al, Hypertension 2007 Sabbah et al, Circ Heart Failure 2011 Liao et al, J Cardiovasc Pharmacol 2014 Brandt et al, Clin Res Cardiol 2010 Madershahian et al, Europace 2014 Gronda et al, Eur J HF 2014 Abraham et al, ACC Featured Clinical Research, March 2015 Zile et al, HRS Late Breaking Clinical Trials, May 2015 Zile et al, ESC-HF Late Breaking Clinical Trials, May 2015 Abraham et al, J Am Coll Cardiol HF 2015 Zile et al, Eur J Heart Failure 2015 Weaver et al, Seminars in Thoracic and CV Surgery 2016 Prospective Subgroup Analysis Justification for Phase III BeAT-HF Randomized, Controlled Clinical Trial in progress Morbidity / Mortality; n = 480 FDA Expedited Access Pathway for early approval Ram VS, J Clin Hypertension 2010 Briasoulis A, Bakris G, Eurointervention 2013 Borisenko et al, J Hypertension 2013 Lohmeier et al, Hypertension 2004, 2005, 2009, 2011, 2012 Schmidli et al, Vascular 2007 Mohaupt et al, Hypertension 2007 Illig et al, J Vasc Surgery 2006 Sanchez et al, Ann Vasc Surgery 2009 Wustmann et al, Hypertension 2009 de Leeuw et al, JACC 2010 Heusser et al, Hypertension 2010 Bisognano et al, JACC 2011 Bakris et al, JASH 2012 Hoppe et al, JASH 2012 Alnima et al, Hypertension 2013 Wallbach et al, Am J Nephrol 2014 de Leeuw et al, Hypertension 2014 Wallbach et al, Hypertension 2016 Barostim Hypertension Pivotal Trial Unconditional IDE approval RCT; n = 240

4 Phase II Randomized Study- BAT for HFrEF: Safety Endpoints System- or Procedure-Related Major Adverse Neurological or Cardiovascular Events (MANCE) 6 months 97% Event-Free Rate 71 Subjects Implanted 2 Pocket hematomas (1 and 7 days from implant) BAT does not cause hypotension in patients with advanced heart failure No symptomatic hypotension SBP significantly increased in BAT group; DBP unchanged BAT is compatible with co-existing cardiac rhythm management devices JACC-HF 3:487-96, 2015

5 CRT vs no-crt: 6 Minute Hall Walk (MHW) Distance 6 Month Change from Baseline Meters Improvement BAT 85.5 no-crt Euro J Heart Failure 17: , Control BAT 16.4 p = p = 0.38 p = 0.01 CRT -3.5 Control

6 CRT vs no-crt: Minnesota Living with Heart Failure (MLWHF) Score 6 Month Change from Baseline Improvement Euro J Heart Failure 17: , p < p = 0.23 p = 0.04 BAT Control BAT Control no-crt CRT

7 6 Months Change from Baseline pg/ml CRT vs no-crt: NT-proBNP -97 [-505, 93] BAT no-crt Euro J Heart Failure 17: , [-74, 700] 79.8 [-452, 402] p = 0.03 p = 0.16 Control p = 0.59 BAT CRT 433 [64, 537] Control

8 Twelve month (Durable) change from baseline no-crt Parameter BAT + GDMT (N/Value) GDMT (N/Value) Repeated Measures Model P-value SBP (mmhg) ± ± ± NTproBNP (pg/ml) (-1141, 134) (-314, 866) MHW (meters) ± ± ± QOL (points) ± ± ± 4.6 <0.001 Weaver et al, Seminars in Thoracic and Cardiovascular Surgery, 2016

9 Summary Phase II Randomized Study- BAT for HFrEF Baroreflex Activation Therapy is safe in HFrEF patients. BAT significantly improves: quality of life score exercise capacity NT-proBNP possibly the burden of HF hospitalizations. Results were most pronounced in No-CRT patients. Results are durable (12 months F/U).

10 Phase III -- Beat-HF Study: Randomized, Controlled Trial of Baroreflex Activation Therapy (BAT) in Patients with HFrEF Ineligible for CRT Presentation Goals Clinical Evidence for Development in Heart Failure Novel Trial Design Expedited Access Pathway for Premarket Approval (EAP) Phase I and II Statistical Analysis (Frequentist and Bayesian) Enrollment Criteria (Revision D) Status of BEAT-HF Study 10

11 Baroreflex Activation Therapy for Heart Failure (BeAT HF) Develop valid scientific evidence for safety and effectiveness of Baroreflex Activation Therapy in heart failure with a reduced EF: NYHA functional Class II-III Left ventricular ejection fraction 35% GDMT Excludes eligible for, or treatment with, CRT

12 FDA Expedited Access Pathway (EAP) Established for therapies intended to treat a life-threatening or irreversibly debilitating disease and that demonstrate the potential to address unmet medical needs FDA may, as a basis for approval, rely on assessments of a device s effect on an intermediate or surrogate endpoint Improvement according to an intermediate endpoint is generally of value to patients even if this does not lead to reduced morbidity or mortality, and could be considered as a basis for marketing approval by FDA. April 23, 2014

13 Endpoint Strategy: EAP Approved Approach 6MHW, MLWHF NT-proBNP Approval (Symptom Improvement) F/up (6 mo) Regulatory Submission Phase 1 Phase 2 First 264 randomized subjects Randomize 480 subjects M&M Trending Follow up (320 events) M&M Regulatory Submission M&M Interim Analysis Sample Size Re-estimation Approval (Outcomes Improvement) Sample Size Analysis Timing Clinical Evidence Phase 1 N = 264 randomized subjects Subjects (N=264) complete six months of follow-up (enrollment continues) Safety evaluation NT-proBNP Six minute hall walk Minnesota living with heart failure (QOL) Accumulated morbidity and mortality trend Phase 2 N = 480 randomized subjects (N=264 subjects from Phase 1 + additional N=216 new subjects) Sufficient morbidity and mortality data collected on all subjects (320 events collected) Full morbidity and mortality Totality of evidence

14 Indication for Use Statements Phase 1 Reduction of the symptoms of heart failure patients who remain symptomatic (NYHA Functional Class III), LVEF 35%, despite GDMT, neither eligible for nor treated with CRT. Phase 2 Indicated for treatment of patients with heart failure. Heart failure is defined as: NYHA functional Class III, LVEF 35% despite GDMT, including subjects neither eligible for nor treated with CRT.

15 Statistical Analysis Approaches Frequentist Analyses of Phase 1 Endpoints (Symptom-Limited Approval) Final analysis Phase 2 Morbidity and Mortality Endpoint (M&M Approval) Bayesian Predictive probability calculations probability of a significant final M&M analysis conditional on M&M events up to end of Phase I, Phase I endpoints (longitudinal model), and baseline events before trial entry - Part of Symptom-Limited Approval - Also used in sample size decisions

16 Endpoint Strategy: EAP Approved Approach 6MHW, MLWHF NT-proBNP Approval (Symptom Improvement) F/up (6 mo) Regulatory Submission Phase 1 First 264 randomized subjects M&M Trending By the end of Phase I F/U, Phase II recruitment is complete By PMA approval for Phase I, Phase II F/u is complete Phase 2 Randomize 480 Subjects Follow up (320 events) M&M Regulatory Submission M&M Interim Analysis Sample Size Re-estimation Approval (Outcomes Improvement)

17 Enrollment Criteria Heart Failure NYHA Class II or III; For Class II, NYHA Class III within 3 months prior to enrollment. LVEF 35% 6MHW 150 m AND 400 m Natriuretic Peptide BNP 100 or NT-proBNP 400, BNP/NT-proBNP measured as outpatient when subject is clinically stable. If taking sacubitril/valsartan (i.e. Entresto), NT-proBNP must be used OR HF hospitalization in past 12 months. HF hospitalization includes an overnight hospital or hospital-based observation unit or an emergency room. 17

18 Screening and Baseline Procedures Procedure Screen Baseline Comment Subject Informed Consent X Demographics/Medical History X Physical Assessment X X Pregnancy test when appropriate Subject Medications X X Adverse Events X X LVEF X* Local Six Minute Hall Walk X* X BNP or NT-proBNP X* Local Core lab NT-proBNP X Shipped corelab Serum egfr X Local Carotid Duplex Ultrasound X Local, historical value accepted AHA/ACC Stage X NYHA Classification X* X Voice / Eating Tool X Electrocardiography (ECG) X Local MLHF and EQ-5D Questionnaires X Patient completed CRM Arrhythmia Log O Previous 12 months 18

19 Follow-Up Procedures Months from Implant Procedure * After 24*** Physical Assessment X X X X X X X X X X Subject Medications X X X X X X X X X X Adverse Events X X X X X X X X X X Six Minute Hall Walk X X Core lab NT-proBNP X X NYHA Classification X X X** MLWHF Questionnaire X X X** EQ-5D Questionnaire X X X** CRM Arrhythmia Log O O O** O Device Programming X X X X X X X X 19

20 Phase III Beat-HF Study: Randomized, Controlled Trial of Baroreflex Activation Therapy (BAT) in Patients with HFrEF Ineligible for CRT Presentation Goals Clinical Evidence for Development in Heart Failure Novel Trial Design Status of BEAT-HF Study 20

21 Patient Status Flow Chart Enrolled n=364 Pending n=29 Randomized n=132 Screening Failure n=203 Medical Management Arm n=65 Device Arm n=67 Withdrawn prior to implant n=4 Implanted n=56 Pending n=7

22 US Sites Status Sept 22 nd 77 sites active 364 enrollments (60 sites) 132 randomizations (45 sites) No subjects enrolled At least 1 subject enrolled At least 1 subject randomized Confidential 22

23 Patient Recruitment Status Number of Subjects Enrolled Randomized Screening Failure Still Being Tested 0 Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug

24 Enrollment / Randomization Data Number of Enrollments Number of Randomizations Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep 0 Apr May Jun Jul Aug Sep Oct 10:28 Nov Dec Jan Wednesday, Feb Mar Apr May Jun September Jul Aug 20, 2017 Number of Subjects Total Years of Follow-Up Number of Events Events per Year Primary Endpoint Event Rate

25 BeAT-HF Study Timeline 6MHW, MLWHF NT-proBNP F/up (6 mo) Phase 1 First 264 Randomized Subjects M&M Trending April 2016 May 2018 November 2018 April 2019 Oct 2021 Phase 2 Randomize 480 Subjects Events (n=320)

26 Baseline Demographics Race Variable N Mean ± SD or N (%) Range Asian (3.8%) N/A Black or African American (22.0%) N/A White (64.4%) N/A Other (6.8%) N/A Unknown or Not Reported (3.0%) N/A Female (16.7%) N/A Age (years) ± Age>= (44.7%) N/A BMI (kg/m2) ± SBP (mmhg) ± DBP (mmhg) ± HR (bpm) ± LVEF (%) ±

27 Baseline Characteristics Variable N Mean ± SD or N (%) Range BNP (pg/ml) median (IQR) (182, 782) NT-proBNP (pg/ml) median (IQR) (638, 3744) BNP>=400 or NT-proBNP>=1600 median IQR) (46.0%) N/A 100<=BNP<400 or 400<=NT-proBNP<1600 AND HF Hosp (33.9%) N/A NYHA: Class III (93.2%) N/A 6 Minute Walk (m) ± egfr ± QRS Interval ± LBBB (3.0%) N/A A Fib (screening ECG) (9.8%) N/A A Fib (medical history) (36.4%) N/A Paroxysmal A Fib (medical history) (27.3%) N/A Permanent A Fib (medical history) (4.5%) N/A Persistent A Fib (medical history) (4.5%) N/A At Least One HF Hospitalization (64.4%) N/A Number of HF Hospitalizations ±

28 Baseline Medications Variable N Mean ± SD or N (%) Range Number of Meds ± ACE-I/ARB Use (61.4%) N/A Beta-Blocker Use (93.9%) N/A Diuretic Use (92.4%) N/A Ivabradine Use (3.0%) N/A MRA Use (50.0%) N/A Entresto Use (21.2%) N/A Other HF Meds Use (40.9%) N/A ICD (82.6%) N/A PM (13.6%) N/A Other cardiac device (e.g., CardioMEMS) (3.8%) N/A ACE-I/ARB Percent of Max Daily Dose ± Beta-Blocker Percent of Max Daily Dose ± Diuretic Percent of Max Daily Dose ± MRA Percent of Max Daily Dose ±

29 Take Home Conclusions Baroreflex Activation Therapy (BAT) Provides: Novel approach to management of HFrEF Integrated Autonomic Nervous System Response Inhibits Sympathetic Activity Enhances Parasympathetic Activity Innovative and stepwise development program Preclinical through Phase III EU/US Phase II robust evidence of safety and efficacy Europe: CE Mark indication US: Phase III ongoing Beat-HF Study under Expedited Access Pathway 29

30 The Medical University of South Carolina Thank you. 30

Baroreflex Activation Therapy: Integrated Autonomic Neuromodulation for Heart Failure and Hypertension

Baroreflex Activation Therapy: Integrated Autonomic Neuromodulation for Heart Failure and Hypertension Robert S. Kieval, VMD, PhD Founder & Chief Technology Officer, CVRx, Inc. Financial Disclosure I,